tbuckley/cabot-search huggingface dataset:
Abstract 5643: YK-2168, a potent and selective small molecule CDK9 inhibitor
Authors: Charles Z. Ding, Yingchun Liu, Wang Zhou
Journal: Cancer Research (2022)

Abstract Objective: Cyclin-dependent kinase 9 (CDK9), which regulates transcriptional elongation, is an attractive therapeutic target for many cancers, especially for cancers driven by transcriptional dysregulation. Specifically, CDK9 mediated transcriptional regulation of short-lived antiapoptotic proteins is critical for the survival of transformed cells. Emerging evidence indicates that selective CDK9 inhibition may provide a therapeutic benefit against certain cancers. We disclose here for the first time a novel CDK9 inhibitor YK-2168 a clinical candidate and its preclinical results. Method: The biochemical activities of YK-2168 for CDK9, CDK1 and CDK2 were measured by literature methods (Tinggui, 2014). The in vitro anti-proliferative activity was evaluated on selected leukemia cell line MV4-11, lymphoma cell line Karpas422 and gastric carcinoma cell line SNU16. The in vivo antitumor activity of YK-2168 was evaluated in cell-derived xenograft (CDX) models of Leukemia (MV4-11) and gastric carcinoma (SNU16), YK-2168 was administered by intravenous (IV) injection. PK/PD was assessed by western blot analysis of pS2-RNA Pol ll CTD expression and cleaved caspase 3 level in the treated tumor tissues. Result: YK-2168 displayed potent selective inhibitory biochemical activity for CDK9 (IC50 : 7.5 nM), but that of CDK1 and CDK2 were modest (IC50 : 466.4 and 361.1 nM), indicative of good selectivity for CDK9. It also showed good anti-proliferative activities in tumor cell lines of different types, MV4-11 potency IC50 of 53.4 nM, Karpas422 potency IC50 of 91.1 nM, and SNU16 potency IC50 of 88.3 nM. YK-2168 showed in vivo antitumor activity in a MV4-11 CDX model with TGI =80 % @10 mpk QW (IV with 4 doses), compared with the same dose of BAY1251152 (TGI =65 % @10 mpk, QW). YK-2168 also showed good regressive antitumor activity in vivo in a SNU16 CDX model with TGI =115 % @10 mpk QW (while BAY1251152 totally inhibited growth with TGI =100%). Western blot analysis of the tumor samples showed that YK-2168 can also inhibit the expression of CDK9 downstream signal proteins and induced apoptosis in a dose-dependent manner. Conclusion: We have discovered a potent and selective small molecule CDK9 inhibitor YK-2168, which showed potent CDK9 inhibition and strong antitumor activity in both in vitro and in vivo preclinical tumor models. These results together with GLP safety results are considered highly promising and warrant moving the compound forward to clinical investigation. In fact, YK-2168 was granted phase I clinical trials in both US and China. Citation Format: Charles Z. Ding, Yingchun Liu, Wang Zhou. YK-2168, a potent and selective small molecule CDK9 inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5643.
Abstract 4239: Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade
Authors: Marvin O'ketch, Victoria A. Love, Jeffrey A. Kiefer, David W. Lee, Lizette A. Castaño, Spyro Mousses, David O. Azorsa
Journal: Cancer Research (2022)

Abstract T-cell exhaustion describes the dysfunctional state of effector T cells in the tumor microenvironment that results from chronic and prolonged exposure to antigen. It also represents an important mechanism of clinical resistance to immune checkpoint blockade. Recently, the transcription factor NR4A1 has been shown to be upregulated in tumor-specific T cells and plays a role in driving exhaustion during chronic antigen stimulation of T cells. Pro-oncogenic activities of NR4A1 have long been observed in various solid tumors including colorectal and breast cancers, and co-expression of NR4A1 with known immune checkpoint markers such as PD-L1 have also been observed in various cancer cell lines. These findings have identified NR4A1 as an important target for overcoming resistance to cancer immunotherapy. We hypothesize that multi-targeting to simultaneously block PD-1 signaling and silence NR4A1 gene expression can reverse T-cell exhaustion and expand the clinical benefit of PD-1 blockade in immune therapy resistant solid tumors. Using our SeekR™ RNA therapeutics platform, we combined aptamer binders to PD-1 with siRNA against NR4A1, andNR4A1 and evaluated their ability to reverse T-cell exhaustion and re-activate T-cell based anticancer immunity in solid tumors. Specifically, we created SeekR™ therapeutic RNA molecules with dual flanking RNA aptamers binders to PD-1 and other checkpoint inhibitors, connected by a double stranded bridge that encodes for siRNA silencers that target multiple immunomodulatory genes, such as NR4A1. The novel anti-PD-1 RNA aptamer component serve to: A) direct and deliver the SeekR™ RNA oligo therapeutics to exhausted T-cells that express PD-1 receptors; and B) internalize the siRNA component into the T-cells. The siRNA components of the SeekR™ serve to silence NR4A1 which lead to reversal of the cytotoxic T-cell exhausted phenotype following chronic in-vitro stimulation. These results demonstrate that dual targeting of PD-1 and NR4A1 has the potential to reverse T-cell exhaustion and the potential to overcome cancer immunotherapy resistance in the clinic. Citation Format: Marvin O'ketch, Victoria A. Love, Jeffrey A. Kiefer, David W. Lee, Lizette A. Castaño, Spyro Mousses, David O. Azorsa. Development of multi-targeting immunomodulatory SeekR RNA therapeutics to overcome resistance to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4239.
Abstract 4215: Combination of STING and TLR 7/8 agonists as vaccine adjuvants for cancer immunotherapy
Authors: Shubhmita Bhatnagar, Vishnu Revuri, Manan Shah, Peter Larson, David Ferguson, Jayanth Panyam
Journal: Cancer Research (2022)

Abstract Various classes of molecules including toll-like receptor (TLR) agonists, exosomes, and metallo compounds have been evaluated as adjuvants for cancer vaccines. However, their wide-spread clinical use has been limited by transient immune responses and serious side-effects. Here, we propose the use of a multi-adjuvant approach that combines two different classes of adjuvants, STING and TLR 7/8 agonists, based on their distinct immune cell targets, signalling pathways, and significant roles in the activation and maintenance of immune responses. We evaluated the potential of combining 522, a novel TLR 7/8 agonist, and DMXAA, a STING agonist, for stronger DC activation and greater CD8 T cell responses. Mouse bearing B16F10-OVA (murine melanoma cell line which expresses ovalbumin) tumors were immunized with OVA mixed with 522 or DMXAA or a combination of 522 and DMXAA daily for 5 days. Immunization with OVA+DMXAA+522 resulted in significant tumor growth inhibition (p &amp;lt; 0.05) and improved survival (p&amp;lt;0.05) compared to other controls. Using flow cytometry, the costimulatory molecule expression and immune cell infiltration in mouse lymph node, spleen and tumor were evaluated. Immunization with OVA+DMXAA+522 resulted in the activation of antigen presenting cells (APCs) in lymph nodes, spleen and tumor (additive or equivalent to single treated groups). The combination also elicited stronger antigen specific CD8 T cell and natural killer (NK) cell responses than control or individual treatment groups. OVA + DMXAA+ 522 immunization increased the number of OVA-specific CD44high CD8 T cells by over 4-fold compared to other treatment groups and control mice in spleen and lymph nodes. A reduction in the frequency of M2 macrophages was observed with OVA+DMXAA+522 treatment. Cytokine analysis demonstrated higher levels of pro-inflammatory cytokines like IFNγ and lower levels of pro-tumorigenic cytokines in the serum of OVA+DMXAA+522 immunized mice compared to that in untreated or OVA-only treated mice. Taken together, these results suggest that combination of TLR7/8 and STING agonists is a promising multi-adjuvant approach for cancer vaccination Citation Format: Shubhmita Bhatnagar, Vishnu Revuri, Manan Shah, Peter Larson, David Ferguson, Jayanth Panyam. Combination of STING and TLR 7/8 agonists as vaccine adjuvants for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4215.
New, shorter treatments for drug resistant TB are a lifeline for people living through conflict
Authors: Lakshmi Jain
Journal: BMJ (2022)

New, shorter treatments drug resistant TB are a lifeline for people living through conflict Lakshmi Jain HIV/TB/hepatitis programme implementer On a recent visit to a camp for internally displaced people in South Sudan, I was asked to help treat a patient with drug resistant tuberculosis (DR-TB).Their life since they had been diagnosed with TB had been far from straightforward.When we asked them how we could help, it became clear that having TB was only one of the many challenges they faced.
Correction:<i>periendoscopic management of direct oral anticoagulants: a prospective cohort study</i>
Journal: Gut (2019)

The last two lines of the results section of the abstract should read: The incidence of delayed bleeding appeared similar in patients who resumed anticoagulation according to BSG/ESGE guidelines or later (6.6% vs 7.7%, p=0.76), but it tended to increase when DOAC was resumed earlier (14.3% vs 6.6%, p=0.27).The risk of delayed major bleeding was significantly higher in patients receiving heparin bridging than in non-bridged ones (26.7% vs 5.9%, p=0.017).
Serum exosome <scp>inflamma‐miRs</scp> are surrogate biomarkers for asthma phenotype and severity
Authors: Sara Vázquez‐Mera, Laura Martelo‐Vidal, Pablo Miguéns‐Suárez, Paula Saavedra‐Nieves, Pilar Arias, Coral González‐Fernández, Mar Mosteiro‐Añón, María Dolores Corbacho‐Abelaira, Marina Blanco‐Aparicio, Paula Méndez‐Brea, Francisco Javier Salgado, Juan José Nieto‐Fontarigo, Francisco Javier González‐Barcala
Journal: Allergy (2022)

Abstract Background Asthma is a heterogeneous disease with several phenotypes, endotypes and severity degrees, in which different T‐cell subpopulations are involved. These cells express specific miRNAs (i.e. inflamma‐miRs) that can be released to serum in exosomes after activation and be used as biomarkers of underlying inflammation. Thus, we aim to evaluate specific T‐cell miRNA signatures in serum exosomes from different subgroups of asthmatic patients. Methods Samples from healthy donors ( N = 30) and patients ( N = 119) with different asthma endotypes (T2 high ‐Atopic/T2 high ‐Non‐atopic/T2 low ) and severity degrees (mild/MA and moderate–severe/MSA) were used. Demographic, clinical, haematological and biochemical characteristics were collected. Twelve miRNAs previously associated with different Th subsets were preselected and their levels in serum exosome samples were measured using RTqPCR. Results We detected five miRNAs with high confidence in serum exosomes: miR‐16‐5p, miR‐21‐5p, miR‐126‐3p, miR146a‐5p and miR‐215‐5p. All of them, except miR‐16‐5p were upregulated in MSA patients compared to MA. A logistic regression model including each of these miRNAs was created to discriminate both conditions, rendering a ROC curve AUC of 0.896 (0.830–0.961). miR‐21‐5p and miR‐126‐3p, both involved in Th1/Th2 differentiation, were specifically augmented in T2 high ‐Atopic patients. Of note, all these changes were found in samples collected in autumn. On the contrary, IL‐6 high patients with MSA, which were more obese, older, with higher neutrophil and basophil counts and TNF levels, displayed a decrease of miR‐21‐5p, miR‐126‐3p and miR‐146a‐5p. Conclusion Immune‐related miRNAs, including miR‐21‐5p, miR‐126‐3p, miR‐146a‐5p and miR‐215‐5p, can be used as clinically relevant non‐invasive biomarkers of the phenotype/endotype and severity of asthma.
TDO2+ myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma
Authors: Simeng Hu, Huanzi Lu, Wenqiang Xie, Dikan Wang, Zhongyan Shan, Xudong Xing, Xiang-Ming Wang, Juan Fang, Wei Dong, Wenxiao Dai, Junyi Guo, Yanshu Zhang, Shuqiong Wen, Xin-Yu Guo, Qianming Chen, Fan Bai, Zhi Wang
Journal: Journal of Clinical Investigation (2022)

Characterization of the dynamic change in the immunological landscape during malignant transformation from precancerous lesions to cancerous lesions in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here, we performed single-cell RNA-Seq (scRNA-Seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 samples of precancerous oral leukoplakia, and 8 adjacent normal samples. We found that tumor-infiltrating CD4+ and CD8+ T cells were functionally inhibited by immunosuppressive ligands expressed on various types of myeloid cells or neutrophils in the process of oral carcinogenesis. Notably, we identified a subset of myofibroblasts that exclusively expressed tryptophan 2,3-dioxygenase (TDO2). These TDO2+ myofibroblasts were located distally from tumor nests, and both CD4+ and CD8+ T cells were enriched around them. Functional experiments revealed that TDO2+ myofibroblasts were more likely to possess the ability for chemotaxis toward T cells but induced the transformation of CD4+ T cells into Tregs and caused CD8+ T cell dysfunction. We further showed that use of the TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored the T cell antitumor response, and prevented the progression of OSCC malignant transformation in murine models. Our study reveals a multistep transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.
An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE)
Authors: Erin E. Gaughan, Tom M. Quinn, Andrew Mills, Annya M. Bruce, Jean Antonelli, Alison C. MacKinnon, Vassilios Aslanis, Feng Li, Richard O’Connor, Cecilia Boz, Ross Mills, Philip Emanuel, Matthew Burgess, Giulia Rinaldi, Asta Valanciute, Bethany Mills, Emma Scholefield, Gareth Hardisty, Emily Gwyer Findlay, Richard A. Parker, John Norrie, James W. Dear, Ahsan R. Akram, Oliver Koch, Kate Templeton, David H. Dockrell, Timothy S. Walsh, Stephen Partridge, Duncan Humphries, Jie Wang-Jairaj, Robert J. Slack, Hans Schambye, De Phung, Lise Gravelle, Bertil Lindmark, Manu Shankar-Hari, Nikhil Hirani, Tariq Sethi, Kevin Dhaliwal
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis.
The systemic anti-microbiota IgG repertoire can identify gut bacteria that translocate across gut barrier surfaces
Authors: Ivan Vujkovic-Cvijin, Hugh C. Welles, Connie W. Y. Ha, Lutfi Huq, Shreni Mistry, Jason M. Brenchley, Giorgio Trinchieri, Suzanne Devkota, Yasmine Belkaid
Journal: Science Translational Medicine (2022)

Unique gut microbiota compositions have been associated with inflammatory diseases, but identifying gut bacterial functions linked to immune activation in humans remains challenging. Translocation of pathogens from mucosal surfaces into peripheral tissues can elicit immune activation, although whether and which gut commensal bacteria translocate in inflammatory diseases is difficult to assess. We report that a subset of commensal gut microbiota constituents that translocate across the gut barrier in mice and humans are associated with heightened systemic immunoglobulin G (IgG) responses. We present a modified high-throughput, culture-independent approach to quantify systemic IgG against gut commensal bacteria in human serum samples without the need for paired stool samples. Using this approach, we highlight several commensal bacterial species that elicit elevated IgG responses in patients with inflammatory bowel disease (IBD) including taxa within the clades
Fitness Landscape Analysis of a tRNA Gene Reveals that the Wild Type Allele is Sub-optimal, Yet Mutationally Robust
Authors: Tzahi Gabzi, Yitzhak Pilpel, Tamar Friedlander
Journal: Molecular Biology and Evolution (2022)

Abstract Fitness landscape mapping and the prediction of evolutionary trajectories on these landscapes are major tasks in evolutionary biology research. Evolutionary dynamics is tightly linked to the landscape topography, but this relation is not straightforward. Here, we analyze a fitness landscape of a yeast tRNA gene, previously measured under four different conditions. We find that the wild type allele is sub-optimal, and 8–10% of its variants are fitter. We rule out the possibilities that the wild type is fittest on average on these four conditions or located on a local fitness maximum. Notwithstanding, we cannot exclude the possibility that the wild type might be fittest in some of the many conditions in the complex ecology that yeast lives at. Instead, we find that the wild type is mutationally robust (“flat”), while more fit variants are typically mutationally fragile. Similar observations of mutational robustness or flatness have been so far made in very few cases, predominantly in viral genomes.
A novel CD19/CD22/CD3 trispecific antibody enhances therapeutic efficacy and overcomes immune escape against B-ALL
Authors: Lijun Zhao, Shuhong Li, Xiaoyi Wei, Xuexiu Qi, Dong Liu, Lei Liu, Feiqiu Wen, Ji-shuai Zhang, Feng Wang, Ze-lin Liu, Yu J. Cao
Journal: Blood (2022)
Immunothrombosis and vascular heterogeneity in cerebral cavernous malformation
Authors: Maria A. Globisch, Favour C. Onyeogaziri, Suvi Jauhiainen, Anthony C. Y. Yau, Fabrizio Orsenigo, Lei L. Conze, Maximiliano Arce, Monica Corada, Ross O. Smith, Charlotte Rorsman, Veronica Sundell, Dinesh Fernando, Geoffrey Daniel, Oscar Mattsson, Henri Savander, Alkwin Wanders, Behnam Rezai Jahromi, Aki Laakso, Mika Niemelä, Elisabetta Dejana, Peetra U. Magnusson
Journal: Blood (2022)

Cerebral cavernous malformation (CCM) is a neurovascular disease that results in various neurological symptoms. Thrombi have been reported in surgically resected CCM patient biopsies, but the molecular signatures of these thrombi remain elusive. Here, we investigated the kinetics of thrombi formation in CCM and how thrombi affect the vasculature and contribute to cerebral hypoxia. We used RNA sequencing to investigate the transcriptome of mouse brain endothelial cells with an inducible endothelial-specific Ccm3 knock-out (Ccm3-iECKO). We found that Ccm3-deficient brain endothelial cells had a higher expression of genes related to the coagulation cascade and hypoxia when compared with wild-type brain endothelial cells. Immunofluorescent assays identified key molecular signatures of thrombi such as fibrin, von Willebrand factor, and activated platelets in Ccm3-iECKO mice and human CCM biopsies. Notably, we identified polyhedrocytes in Ccm3-iECKO mice and human CCM biopsies and report it for the first time. We also found that the parenchyma surrounding CCM lesions is hypoxic and that more thrombi correlate with higher levels of hypoxia. We created an in vitro model to study CCM pathology and found that human brain endothelial cells deficient for CCM3 expressed elevated levels of plasminogen activator inhibitor-1 and had a redistribution of von Willebrand factor. With transcriptomics, comprehensive imaging, and an in vitro CCM preclinical model, this study provides experimental evidence that genes and proteins related to the coagulation cascade affect the brain vasculature and promote neurological side effects such as hypoxia in CCMs. This study supports the concept that antithrombotic therapy may be beneficial for patients with CCM.
Targeting FLT3 with a new-generation antibody-drug conjugate in combination with kinase inhibitors for treatment of AML
Authors: Maike Roas, Binje Vick, Marc-André Kasper, Marina Able, Harald Polzer, Marcus Gerlach, Elisabeth Kremmer, Judith S. Hecker, Saskia Schmitt, Andreas Stengl, Verena Waller, Natascha Hohmann, Moreno Festini, Alexander Ludwig, Lisa Rohrbacher, Tobias Herold, Marion Subklewe, Katharina S. Götze, Christian P. R. Hackenberger, Dominik Schumacher, Jonas Helma-Smets, Irmela Jeremias, Heinrich Leonhardt, Karsten Spiekermann
Journal: Blood (2022)

Fms-like tyrosine kinase 3 (FLT3) is often overexpressed or constitutively activated by internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutations in acute myeloid leukemia (AML). Despite the use of receptor tyrosine kinase inhibitors (TKI) in FLT3-ITD-positive AML, the prognosis of patients is still poor, and further improvement of therapy is required. Targeting FLT3 independent of mutations by antibody-drug conjugates (ADCs) is a promising strategy for AML therapy. Here, we report the development and preclinical characterization of a novel FLT3-targeting ADC, 20D9-ADC, which was generated by applying the innovative P5 conjugation technology. In vitro, 20D9-ADC mediated potent cytotoxicity to Ba/F3 cells expressing transgenic FLT3 or FLT3-ITD, to AML cell lines, and to FLT3-ITD-positive patient-derived xenograft AML cells. In vivo, 20D9-ADC treatment led to a significant tumor reduction and even durable complete remission in AML xenograft models. Furthermore, 20D9-ADC demonstrated no severe hematotoxicity in in vitro colony formation assays using concentrations that were cytotoxic in AML cell line treatment. The combination of 20D9-ADC with the TKI midostaurin showed strong synergy in vitro and in vivo, leading to reduction of aggressive AML cells below the detection limit. Our data indicate that targeting FLT3 with an advanced new-generation ADC is a promising and potent antileukemic strategy, especially when combined with FLT3-TKI in FLT3-ITD-positive AML.
Leukemia inhibitory factor protects against graft-versus-host disease while preserving graft-versus-leukemia activity
Authors: Jianming Wang, Chun-Yuan Chang, Xue Yang, Fan Zhou, Juan Liu, Sining Zhu, Xue-Zhong Yu, Chen Liu, Timothy E. O’Sullivan, Ping Xie, Zhaohui Feng, Wenwei Hu
Journal: Blood (2022)